Despite increasing global efforts to understand the pathogenesis of specific airway diseases, including a growing number of transcriptomics and genome-wide association studies, mechanisms linked to development of asthma remain elusive. Asthma is frequently associated with co-morbid diseases of the upper airways, allergic rhinitis and chronic rhinosinusitis. These observations have led to the unified airway hypothesis that the upper and lower airway may be immunologically linked, supported by the fact that all airways form a continuous mucosal epithelial barrier interacting with the environment. Moreover, epithelial barrier disruption has been recently implicated as central to the development of allergic disease. Approaching asthma as a barrier disease of the unified airway is one strategy that could provide a deeper understanding of its pathogenesis. Using a novel comparative multi-study bioinformatics approach, we have identified novel genes (including ELF5, FGFR2, KLF4, SNAI2, TGM2 and WNT4) and several unrecognized and exciting biological themes supporting the unified airway concept. Our preliminary testing of these processes suggests that they converge on an underlying mechanism promoting epithelial de-differentiation that is likely driven by aberrant integration of developmental and nuclear hormonal signaling for epithelial homeostasis. We have assembled a strong cross-disciplinary team to test the unified airway hypothesis, which holds that common systemic processes underlie pathology of allergic disease at both airway locations, with the following specific goals: 1) to discover novel pathways for asthma and identify genetic signatures of unified airway disease, which would facilitate the study of asthma pathogenesis at either airway location; 2) to confirm mucosal origins of putative biomarkers, validate their expression and test diagnostic utility of these genes in an independent cohort of asthma patients. We are strongly encouraged by our preliminary findings, and anticipate that our novel approaches will provide information that will significantly impact our understanding of the pathogenesis of asthma and allergic diseases of the airway.